When
a medicine is prescribed or administered to a patient, it can have several
effects. Some of them depend directly on the medicine's pharmacological
action. There exists, however, another effect, that is not linked to the
medicine's pharmacology, and that can also appear when a pharmacologically
inactive substance is administered. We call it placebo
effect. It is one of the most common phenomena observed in medicine,
but also a very mysterious one.

The placebo effect is powerful. In a
study carried out at the University of Harvard, its effectiveness was tested
in a wide range of disturbances, including pain, arterial hypertension
and asthma. The result was impressive: 30 to 40% of the patients obtained
relief with the use of placebo. Furthermore, the placebo effect is not
limited to medicines but it can appear with any kind of medical procedure.

In a trial to test the value of a surgical
procedure (ligature of an artery in the thorax) to treat angina pectoris
(pain in the chest caused by chronic heart ischemia), the placebo procedure
consisted in anesthetizing the patient and only cutting his skin. The thus
fictiously treated patients showed an 80% improvement while those actually
operated upon only 40%. In other words: placebo acted better than surgery.

What
is the placebo effect? How can it be explained?

In this paper we shall examine the neurobiological
bases of the placebo effect, according to the most recent hypotheses. The
study and better understanding of the placebo effect, and its place in
medicine, has a great importance for the therapeutical act, besides having
great ethical repercussions in medical practice and research. We shall
focus our explanations upon a specific type of placebo, the pharmacological
agent (medicine). But the principia we discuss in this paper can be generalized
to any type of placebo.

What
is the placebo effect?

The word placebo comes from the Latin verb
"placere", that means "to please".A good definition is the following:

"Placebo is any treatment
devoid of specific actions on the patient's symptoms or diseases that,
somehow, can cause an effect upon the patient."

Pay attention to the difference:placebo
is an innocuous treatment. Placebo effect
is the result obtained by the use of a placebo. A placebo effect is not
induced by every placebo. Nevertheless, a placebo effect can only follow
the use of a placebo. Did you get it?

The knowledge about the placebo effect
was very much enlarged with the medical need to perform controlled
clinical trials,a scientific methodology largely used to determine
the therapeutic effectiveness of new medicines.

In these trials a placebo is obligatorily
administered to a control group of patients, and later the results of this
group are compared with those obtained in the group that receives the active
medicine, whose action one intends to demonstrate. The bigger the difference
in the results between the second and the first groups, the bigger the
pharmacological effectiveness of the studied substance.

Very soon these studies made doctors
notice that placebos had much more effects upon the studied diseases than
anticipated. In some cases the placebo side-effects outreached those of
the active medicine...

Consequently, there was a great increase
in scientific researches aiming to clarify what is this effect, why does
it happen, what is its physiological bases, etc..

Since the placebo effect can be a real
one, calling forth beneficial changes in the patient, it can be very useful
in clinical practice. The medical ethics code even allow its use.

Types
of placebo

Placebos are classified in two groups:
inert and actives.

Inert placebo
- are those really devoid of any action, be it pharmacological, surgical,
etc..

Active placebos
- are those that actually have actions, although these actions are not
specific to the disease for which they are administered.

It is said that placebos have a positive
effect when the patients report some improvement in their ailments,
and a negative effect when the patients report
that they are getting worse or that unpleasant side-effects have occurred
(in this last eventuality the placebo is called nocebo,
a word derived from the Latin nocere, meaning inflicting damage)

A very interesting conclusion can be
drawn: all medicines, besides their actual pharmacological effect, have
a placebo effect, and both kinds of effects cannot be easily separated.

What
causes the placebo effect?

Then comes the question: if the placebo
effect does not derive of an action provoked in the patient's organism,
whence does it come from?

Up to now medical science has not fully
explained what is the cause (or causes) of the placebo effect. But it seems
that it is the result of the patient's expectation of an effect.

Haw can that be explained? There are
diverse theories, derived from different psychological schools, that try
to explain that fact. We shall adopt here that theory that seems to be
the most probable one, that of the conditioned reflex.
You sure do remember it: it was discovered when last century was coming
to its close by a Russian physiologist by the name of Ivan Pavlov. In 1902
he won the first Nobel Prize on Medicine. He is widely known because of
the famous experiment on the dog that salivated whenever it heard a bell
(see here a recapitulation about the conduction
of these experiments and what we have learned with them).

The general idea is that the placebo
effects appears as an involuntary conditioned reflex of the patient's body.
We'll next see how this happens.

Conditioned Reflexes

According to Pavlovian theory, the functioning
of the nervous system can be understood as depending on reflexes, that
are responses to stimuli from the external or internal milieu. A sensorial
stimulus, come it from inside or outside the body, reaches a receptor and
modifies the organic conditions, and, consequently, calls forth a motor,
secretory or vegetative response.

There are two types of reflexes: conditioned
and unconditioned.

Unconditioned
reflexes are those with which the animals are born, acquired along
the evolution of their species, that is, their phylogeny. For example,
if we put food in a dog's mouth, saliva begins to flow. This response is
preordained inside the dog's nervous system.

Conditioned reflexes
are those acquired by the animals during their own lifetime, that is, their
ontogeny. These reflexes represent one of the types of learning the nervous
system is capable of. As certain stimuli keeps acting on them, the animals
form conditioned responses to these stimuli. In order these conditioned
responses can appear, they have to be based upon unconditioned ones. In
Pavlov's classical experiment, ringing the bell didn't cause the dog to
salivate initially. But after he repeatedly rang the bell preceding the
unconditioned stimulus (food), the dog began to salivate in response to
the ringing of bell alone.

Pavlov defined conditioned reflex as:

"a temporary nervous connection between
one of the countless factors of the environment and a very well defined
activity of the organism".

In other words, the reflex is a temporary
connection linking an environmental stimulus to an unconditioned reflex,
thus transformed into a conditioned one, turned on by that until then previously
indifferent environmental stimulus.

Modifying
reaction to medicines through conditioning

This is a very important topic to help
us understand the placebo effect. We shall try to make it understandable
through a simple experiment:.

Ilustration: Renato M. E. Sabbatini

After a sound stimulus, acetylcholine
is injected in a dog. Hypotension (lowering of arterial blood pressure)
is the dog's answer to acetylcholine. After several combinations of the
sound with the injection, the dog will still show hypotension, even if
we inject adrenaline instead of acetylcholine. Since it should normally
show hypertension (high blood pressure), this indicates that conditioning
completely modified the response to the second agent. The pharmacological
action of adrenaline was annulled. An increase in the dog's blood pressure
would be the expected reaction to adrenaline injection. Since the animal
receives this injection together with a sound stimulus that, for it, is
a sign of hypotension, its blood pressure keeps lowering. The dog's body
simply ignores the pharmacological action of adrenaline, and obeys the
hypotension signal engraved in its central nervous system.

Very important to point up is the fact
that several environmental stimuli can unite to each other, forming a chain.
Any of those stimuli can act as a sign and turn the conditioned reflex
on. Other environmental stimuli, such as entering the room where the experiment
takes place, seeing the experimenter or hearing his voice (even out of
the room), can thus evoke the same response as the original conditioned
stimulus.

Reflexes
and language in human beings

And what would happen in a human being?
The same thing. There are many experiments showing that man's functions
are as conditionable as those of animals. For instance: patients suffering
intense pains, caused by a disease called arachnoiditis, were relieved
and slept after they received intravenous injections of novocaine (an anesthetic).
After some time, the patients still experienced pain relief and slept,
although weak saline injections, instead of novocaine, were applied.

In man there is something more important
to be considered. According to Pavlov, in animals there exists only what
he called the first system of signals of reality. It is made up of these
brain systems that receive and analyze stimuli that come both from within
and without the organism (for instance, sounds, lights,CO2 levels
in the blood, bowel movements, etc.) .

In human beings, there exists, besides
the first system of signals, a second one, language, that increases the
possibilities of conditioning. For human beings words can function as stimuli,
so real and effective, that they can mobilize us just like a concrete stimulus,
and even more, sometimes. Because words are symbols, abstractions, the
conditioned stimulus can be generalizable.

An example?

If we condition a man applying electric
shocks in his hand after he hears the word bell, a defensive reaction ensues
and he draws out his hand. After some time, hearing the word bell (in his
native tongue or in any other he understands) or seeing a bell (or a picture
of one), will cause this man to draw out his hand. Why? Because this man
was not conditioned to a group of sounds, as in the dog's case, but to
an abstraction, the idea of a bell.

Another example of conditioning in human
beings: electric shocks are applied in a subject's hand after he hears
the word path, causing his hand to be drawn out. After some time, just
hearing the word path is enough to cause the defensive reaction, also induced
by synonyms like road, way, route, etc..

Placebo
effect as a conditioning

Thus we come to a very convincing physiological
explanation about the placebo effect: it is an organic effect that occurs
in the patients due to Pavlovian conditioning on the level of abstract
and symbolic stimuli.

According to this explanation, what
counts is the reality present in the brain, not the pharmacological one.
The nervous system expectation in relation to the effects of a drug can
annul, revert or enlarge the pharmacological reactions to this drug. This
expectation can also cause inert substances to elicit effects that actually
don't depend on them.

We could then define placebo effect
as the therapeutically positive (or negative) result of expectations implanted
in the nervous system of the patients, through conditioning, consequent
to the prior use of medicines, contacts with doctors, and information obtained
by means of reading and remarks of other people.

Conclusions

The placebo effect can be viewed in
two different ways:(I) for those doing clinical trials
to study a new medicine in order to evaluate its real value, the placebo
effect is a nuisance: a group of non-medicamentous effects to be eliminated
whenever possible, with the aid of research techniques;

(II) in medical practice, the placebo
effect can be useful, because those non-medicamentous effects can be beneficial
to the patient. The healing action of specific therapeutic agents, pharmacologically
active, can be reinforced by the placebo effect consequent to expectations
of cure aroused in the patients in the context of a good doctor-patient
relationship. Contrariwise, in the absence of such a good relationship,
an important negative placebo effect can ensue, spoiling the compliance
to the treatment. The patient simply ignores the prescription or takes
the medicines in a completely different way. If he happens to take them
in the prescribed way, he will exaggerate all the possible negative effects
and will ignore the positive effects of the treatment.

To conclude, we remind that some authors
consider that the placebo effect has a dark side, because the cures due
to it favor the perpetuation of the use of ineffective and irrational medicinal
therapeutic procedures, as those used in the so-called "alternative medicine".

The
Authors

Júlio Rocha do Amaral, MD - Júlio
Rocha do Amaral, MD – Teacher of clinical pharmacology, anatomy and physiology.
Medical Manager of Merck S/A Indústrias Químicas (pharmaceutical
and chemical industries). Redactor of didactic manuals on anatomy, physiology
and pharmacology used by Merck S/A. Editing supervisor of the following
scientific publications: Senecta, Galenus and Sinapse. Redactor of clinical
trials and protocols since 1978. Assistant coordinator of courses on Oxydology
sponsored by the Human Being Institute and UNIGRANRIO (University
of Great Rio). Head of Psychiatric Service. Neurosciences Department. The
Human Being Institute. Co-author of the book "Principles of Neurosciences"
Email: julioamaral@olimpo.com.br

Renato
M.E. Sabbatini, PhD. holds a doctorate in neurophysiology of behavior
by the School of Medicine of the University of São Paulo at Ribeirão
Preto. He was visiting scholar at the Max Planck Institute of Psychiatry,
Munich, Germany. Currently, Dr. Sabbatini is associate director of the
Center for Biomedical Informatics and associate professor and Chairman
of Medical Informatics of the Medical School of the State University of
Campinas, Campinas, Brazil. Associate Editor of Brain & Mind. Email:
sabbatin@nib.unicamp.br